8-6414878-G-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_024596.5(MCPH1):c.228G>T(p.Val76=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.782 in 1,612,258 control chromosomes in the GnomAD database, including 498,967 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.70 (39458 hom., cov: 29)
  • Exomes 𝑓: 0.79 (459509 hom.)
• Consequence: MCPH1 NM_024596.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -1.21

Genes affected

MCPH1 (HGNC:6954): (microcephalin 1) This gene encodes a DNA damage response protein. The encoded protein may play a role in G2/M checkpoint arrest via maintenance of inhibitory phosphorylation of cyclin-dependent kinase 1. Mutations in this gene have been associated with primary autosomal recessive microcephaly 1 and premature chromosome condensation syndrome. Alternatively spliced transcript variants have been described. [provided by RefSeq, Feb 2010]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 8-6414878-G-T is Benign according to our data. Variant chr8-6414878-G-T is described in ClinVar as [Benign]. Clinvar id is 158851.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-6414878-G-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-1.21 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.796 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MCPH1	NM_024596.5	c.228G>T	p.Val76=	synonymous_variant	3/14	ENST00000344683.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MCPH1	ENST00000344683.10	c.228G>T	p.Val76=	synonymous_variant	3/14	1	NM_024596.5	P1

Frequencies

GnomAD3 genomes AF: 0.702 AC: 106222 AN: 151218 Hom.: 39439 Cov.: 29

Gnomad AFR AF: 0.438

Gnomad AMI AF: 0.858

Gnomad AMR AF: 0.795

Gnomad ASJ AF: 0.699

Gnomad EAS AF: 0.785

Gnomad SAS AF: 0.733

Gnomad FIN AF: 0.891

Gnomad MID AF: 0.661

Gnomad NFE AF: 0.802

Gnomad OTH AF: 0.708

GnomAD3 exomes AF: 0.779 AC: 194367 AN: 249410 Hom.: 77206 AF XY: 0.780 AC XY: 105598 AN XY: 135306

Gnomad AFR exome AF: 0.428

Gnomad AMR exome AF: 0.857

Gnomad ASJ exome AF: 0.691

Gnomad EAS exome AF: 0.787

Gnomad SAS exome AF: 0.741

Gnomad FIN exome AF: 0.893

Gnomad NFE exome AF: 0.799

Gnomad OTH exome AF: 0.786

GnomAD4 exome AF: 0.790 AC: 1154498 AN: 1460924 Hom.: 459509 Cov.: 42 AF XY: 0.790 AC XY: 573782 AN XY: 726748

Gnomad4 AFR exome AF: 0.427

Gnomad4 AMR exome AF: 0.851

Gnomad4 ASJ exome AF: 0.688

Gnomad4 EAS exome AF: 0.785

Gnomad4 SAS exome AF: 0.743

Gnomad4 FIN exome AF: 0.890

Gnomad4 NFE exome AF: 0.802

Gnomad4 OTH exome AF: 0.763

GnomAD4 genome AF: 0.702 AC: 106273 AN: 151334 Hom.: 39458 Cov.: 29 AF XY: 0.709 AC XY: 52402 AN XY: 73858

Gnomad4 AFR AF: 0.438

Gnomad4 AMR AF: 0.796

Gnomad4 ASJ AF: 0.699

Gnomad4 EAS AF: 0.786

Gnomad4 SAS AF: 0.733

Gnomad4 FIN AF: 0.891

Gnomad4 NFE AF: 0.802

Gnomad4 OTH AF: 0.710

Alfa AF: 0.762 Hom.: 55851

Bravo AF: 0.686

Asia WGS AF: 0.747 AC: 2595 AN: 3478

EpiCase AF: 0.784

EpiControl AF: 0.784

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Oct 21, 2013	- -
Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Aug 02, 2017	- -

Microcephaly 1, primary, autosomal recessive Benign:4

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Sep 05, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	Jun 28, 2017	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
Cadd	Benign	0.44
Dann	Benign	0.56

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs2305022; hg19: chr8-6272399;